Silver-Catalyzed Asymmetric Aldol Reaction of Nonactivated Ketones with α-Isocyanocarboxylic Acid Derivatives Enabled by Prolinol-phosphine-<i>sec</i>-amine Chiral Ligand

The catalytic asymmetric aldol reaction of nonactivated ketones is a formidable challenge in asymmetric catalysis. To this end, we designed and synthesized a prolinol-phosphine-sec-amine P,N,N,O-tetradentate chiral ligand that enabled a highly diastereo- and enantioselective silver(I)-catalyzed aldol reaction of nonactivated ketones with isocyanoacetamides, affording enantioenriched α-amino acid derivatives with a tertiary alcohol at the β-position. This stereoselective reaction allowed extremely challenging molecular transformations with sterically demanding dialkyl ketones and alkyl aryl ketones, such as tert-alkyl methyl ketones, sec-alkyl primary alkyl ketones, and sec-alkyl aryl ketones. The silver(I) catalyst system was also effective in the enantiocontrolled construction of consecutive tetrasubstituted stereogenic carbon centers through the aldol reaction between simple aryl alkyl ketones and α-alkyl-α-isocyanoaetates. Spectroscopic and microED analysis combined with computational investigations showed that P,N,N,O-tetradentate metal binding of the chiral ligand allows the creation of a metal/organo cooperative asymmetric catalytic space that provides densely accumulated classical and nonclassical hydrogen bonds and complementary London dispersion interactions, stabilizing the transition state of the stereochemistry-determining ring-closing reaction of the oxyanion intermediate.